Treatments for chronic pulmonary infections caused by nontuberculous mycobacteria (NTM), such as Mycobacterium avium-intracellulare complex (MAC) are both lengthy and complex, and recurrent infection with new strains of mycobacteria or by the original organism often occur. Immunocompromised individuals are the most susceptible to NTM infections and must be primarily considered with the development of new treatments. Here, we propose the development of a novel mouse model that mimics human disease and pathology in immunocompromised hosts and an immunotherapeutic vaccine to combat the global burden of NTM. We hypothesize that host-directed immune responses induced by an immunotherapeutic vaccine regimen may enable clearance of clinically important pulmonary infections, when given as an adjunct to drug treatment. We have developed a subunit vaccine (ID91 protein antigen) combined with a synthetic toll-like receptor 4 (TLR4) agonist adjuvant (GLA-SE), that shows protective efficacy against an aerosol infection with M. avium in a mouse model. In addition to the ID91 subunit vaccine, we have developed a second generation ID91 vaccine and will test this vaccine platform for efficacy against M. avium. We believe that a prime-boost strategy, engaging several arms of immunity will provide more effective and long-lasting immunity against M. avium. Importantly, our ID91 vaccine design uses bacterial antigens that share consensus sequences with BCG and different NTM strains, which we believe may boost waning immune responses in immune-compromised individuals. Furthermore, we will leverage our extensive expertise derived from the development of our first generation candidate vaccine ID93+GLA-SE, currently in Phase 2a clinical testing, to optimize and characterize the candidate ID91-based vaccines, including the novel ID91 vaccine platform. In Aim 1, we will test the efficacy of the first generation and second generation vaccine platforms in a prime-boost strategy against M. avium. Aim 2 will be devoted to the development of an NTM therapeutic mouse model, using immunodeficient Beige mice. In this Aim, we will first determine the in vivo bacterial clearance kinetics of three different drug regimens. Based on efficacy, one of the drug regimens will be further characterized for relapse rates, following different lengths of treatment against M. avium, in the same mouse model. Finally, we will test the optimal vaccine strategy (down selected in Aim 1) as an adjunct to the optimal drug therapy regimen (selected in Aim 2) in the newly developed NTM mouse therapy model. Completion of the Aims in this proposal will lead to the establishment of a novel NTM therapeutic mouse model for further evaluation of new drugs and experimental immunotherapy regimens against pulmonary infection with M. avium.